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Purpose: RTOG 0617 compared standard-dose (SD; 60 Gy) versus high-dose (HD; 74 Gy) radiation with concurrent chemotherapy and determined the efficacy of cetuximab for stage III non-small-cell lung cancer (NSCLC)., Methods: The study used a 2 × 2 factorial design with radiation dose as 1 factor and cetuximab as the other, with a primary end point of overall survival (OS)., Results: Median follow-up was 5.1 years. There were 3 grade 5 adverse events (AEs) in the SD arm and 9 in the HD arm. Treatment-related grade ≥3 dysphagia and esophagitis occurred in 3.2% and 5.0% of patients in the SD arm v 12.1% and 17.4% in the HD arm, respectively ( P = .0005 and < .0001). There was no difference in pulmonary toxicity, with grade ≥3 AEs in 20.6% and 19.3%. Median OS was 28.7 v 20.3 months ( P = .0072) in the SD and HD arms, respectively, 5-year OS and progression-free survival (PFS) rates were 32.1% and 23% and 18.3% and 13% ( P = .055), respectively. Factors associated with improved OS on multivariable analysis were standard radiation dose, tumor location, institution accrual volume, esophagitis/dysphagia, planning target volume and heart V5. The use of cetuximab conferred no survival benefit at the expense of increased toxicity. The prior signal of benefit in patients with higher H scores was no longer apparent. The progression rate within 1 month of treatment completion in the SD arm was 4.6%. For comparison purposes, the resultant 2-year OS and PFS rates allowing for that dropout rate were 59.6% and 30.7%, respectively, in the SD arms., Conclusion: A 60-Gy radiation dose with concurrent chemotherapy should remain the standard of care, with the OS rate being among the highest reported in the literature for stage III NSCLC. Cetuximab had no effect on OS. The 2-year OS rates in the control arm are similar to the PACIFIC trial.

Objectives: Relapsed small cell lung cancer (SCLC) has limited treatment options. Anthracyclines and cyclophosphamide have shown synergy in many tumors. Amrubicin (AMR) and cyclophosphamide both have single-agent activity in SCLC. This phase I trial evaluated the combination of AMR and cyclophosphamide in refractory solid organ malignancies and in relapsed SCLC., Materials and Methods: The primary endpoint was to determine maximum-tolerated dose and dose-limiting toxicities of the combination. Eligible patients were enrolled in sequential dose escalation cohorts in a standard 3+3 design. Treatment consisted of cyclophosphamide IV at 500 mg/m on day 1 with escalating doses of AMR IV on days 1 to 3 (25 to 40 mg/m with increments of 5 mg/m per cohort). Cycles were repeated every 21 days. Exploratory objectives analyzed the presence of NQO1 polymorphisms and topoisomerase IIA amplification and correlation with response., Results: Thirty-six patients were enrolled, of whom 18 patients had SCLC (50%). Maximum-tolerated dose was determined to be dose level 2 (cyclophosphamide 500 mg/m, AMR 30 mg/m) due to grade 4 thrombocytopenia. The main grade 3 to 4 toxicities were hematologic. Efficacy results are available for 34 patients. Partial responses, stable disease, and progressive disease rates in the overall study population were 20.6% (n=7), 38.2% (n=13), and 41.2% (n=14), respectively. Partial response, stable disease, and progressive disease rates in the SCLC patients and 1 patient with extrathoracic small cell were 36.8% (n=7), 26.3% (n=5), and 36.8% (n=7), respectively. There was no correlation between topoisomerase IIA amplification or NQO1 polymorphisms and response., Conclusions: AMR and cyclophosphamide can be safely combined with little activity observed in heavily pretreated SCLC patients.

Background: This randomized, double-blind, phase 2 trial evaluated whether the addition of vandetanib to platinum plus etoposide for previously untreated extensive-stage small cell lung cancer (SCLC) prolonged the time to disease progression in comparison with chemotherapy alone., Methods: Patients with previously untreated extensive-stage SCLC received platinum (cisplatin or carboplatin) with etoposide in combination with vandetanib (100 mg daily) or a placebo for up to 4 total cycles (no maintenance therapy). An initial safety run-in phase was conducted with the first 6 patients enrolled; all these patients received vandetanib with cisplatin and etoposide. With an overall sample size of 68 patients, the study had 80% power to detect a 3-month difference in the time to progression (TTP) from 4 to 7 months (significance level,.10 [1-sided log-rank test])., Results: Seventy-four patients were enrolled between April 2008 and May 2013. Thirty-three patients were ultimately randomized to each arm. The baseline characteristics were well balanced, and the median number of treatment cycles was 4 for each arm. Thirty-one patients in each arm were evaluable for TTP; the median TTP was 5.62 months with vandetanib and 5.68 months with the placebo (P = .9518). The median overall survival was 13.24 months with vandetanib and 9.23 months with the placebo (P = .4577; 33 evaluable patients in each arm). Nonhematologic toxicity was increased with vandetanib versus the placebo. No correlation was seen between vascular endothelial growth factor polymorphisms and outcomes., Conclusions: The addition of vandetanib to platinum and etoposide did not improve outcomes for patients with newly diagnosed extensive-stage SCLC. Toxicity was increased in comparison with chemotherapy alone. Cancer 2017;123:303-311. © 2016 American Cancer Society., (© 2016 American Cancer Society.)

Purpose: To evaluate the efficacy of maintenance sunitinib after chemotherapy for small-cell lung cancer (SCLC)., Patients and Methods: The Cancer and Leukemia Group B 30504 trial was a randomized, placebo-controlled, phase II study that enrolled patients before chemotherapy (cisplatin 80 mg/m(2) or carboplatin area under the curve of 5 on day 1 plus etoposide 100 mg/m(2) per day on days 1 to 3 every 21 days for four to six cycles). Patients without progression were randomly assigned 1:1 to placebo or sunitinib 37.5 mg per day until progression. Cross-over after progression was allowed. The primary end point was progression-free survival (PFS) from random assignment for maintenance placebo versus sunitinib using a one-sided log-rank test with α = .15; 80 randomly assigned patients provided 89% power to detect a hazard ratio (HR) of 1.67., Results: One hundred forty-four patients were enrolled; 138 patients received chemotherapy. Ninety-five patients were randomly assigned; 10 patients did not receive maintenance therapy (five on each arm). Eighty-five patients received maintenance therapy (placebo, n = 41; sunitinib, n = 44). Grade 3 adverse events with more than 5% incidence were fatigue (19%), decreased neutrophils (14%), decreased leukocytes (7%), and decreased platelets (7%) for sunitinib and fatigue (10%) for placebo; grade 4 adverse events were GI hemorrhage (n = 1) and pancreatitis, hypocalcemia, and elevated lipase (n = 1; all in same patient) for sunitinib and thrombocytopenia (n = 1) and hypernatremia (n = 1) for placebo. Median PFS on maintenance was 2.1 months for placebo and 3.7 months for sunitinib (HR, 1.62; 70% CI, 1.27 to 2.08; 95% CI, 1.02 to 2.60; one-sided P = .02). Median overall survival from random assignment was 6.9 months for placebo and 9.0 months for sunitinib (HR, 1.28; 95% CI, 0.79 to 2.10; one-sided P = .16). Three sunitinib and no placebo patients achieved complete response during maintenance. Ten (77%) of 13 patients evaluable after cross-over had stable disease on sunitinib (6 to 27 weeks)., Conclusion: Maintenance sunitinib was safe and improved PFS in extensive-stage SCLC., (© 2015 by American Society of Clinical Oncology.)

This open-label, phase II study evaluated the antitumor activity and safety of sunitinib monotherapy as maintenance treatment following first-line chemotherapy in patients with locally advanced or metastatic non-small cell lung cancer (NSCLC). Following treatment with standard doublet chemotherapy (paclitaxel and carboplatin), patients received oral sunitinib (starting dose 50mg/day) in 6-week cycles (Schedule 4/2: 4 weeks on treatment, 2 weeks off treatment) until disease progression, unacceptable toxicity or withdrawal of consent. The primary endpoint was probability of survival at 1 year ≥55%. Of 84 patients who received first-line chemotherapy, 66 (79%) received sunitinib maintenance therapy (median sunitinib cycles started: 2 [range 1-20]). Probability of survival at 1 year was 40.5% (95% confidence interval [CI]: 29.8, 51.0). Median overall survival was 10.4 months (95% CI: 8.0, 12.2). The objective response rate was 27.4% (95% CI: 18.2, 38.2). The most frequently reported all-causality adverse events of any grade during sunitinib maintenance therapy were fatigue/asthenia (55%), diarrhea (36%), and nausea (32%). These data suggest that maintenance therapy may have value in NSCLC, although the primary endpoint of the study was not met., (Copyright © 2011. Published by Elsevier Ireland Ltd.)

Purpose: We designed a phase II trial to evaluate the efficacy and tolerability of high dose induction chemotherapy with carboplatin and paclitaxel with G-CSF and stem cell support followed by surgical resection and/or chest radiotherapy in patients with stage III non-small cell lung cancer (NSCLC)., Patients and Methods: Patients had pathologically confirmed stage IIIA-IIIB NSCLC, adequate end-organ function, no prior chemotherapy or radiation, and performance status 0-1. Peripheral stem cells were mobilized with G-CSF stimulation on days 1-5 and collected prior to chemotherapy. Chemotherapy consisted of 2 cycles of paclitaxel 250 mg/m(2) over 3h and carboplatin at an AUC 18 on days 11 and 32, each followed by stem cell reinfusion. Stable and responding patients went on to surgical resection (in patients deemed resectable) followed by post-operative radiation, or to conventional chest radiotherapy to 66 Gy in unresectable patients., Results: Twelve patients (11 eligible) were accrued from 1996 to 1999. The 11 patients were predominately male (64%), white (82%), of performance status 0 (64%), and with weight loss less than 5% (55%). The median age was 51 (range 31-63). Ten (10) patients (91%) experienced grade 4 toxicity. There were no lethal toxicities. Grade 3-4 toxicities most commonly reported included: platelets (100%), lymphocytopenia (91%), leukopenia (91%), neutropenia (73%), anemia (55%), pain (45%), and nausea (27%). Three patients (27%) had a partial response to induction chemotherapy. Of the 11 patients, 7 underwent surgical exploration, and 10 received radiation. Two patients were completely resected, 3 patients had incomplete resections, and 2 patients had no resection. There were 4 complete responses and 3 partial responses following surgery and/or radiation. The median overall survival time was 17.8 months. The median failure-free survival time was 8.3 months. One-year and 2-year overall survival are estimated at 64% and 27%, respectively., Conclusions: High dose induction chemotherapy with carboplatin and paclitaxel and stem cell support in patients with stage IIIA-IIIB NSCLC produced response rates and survival similar to standard therapy. Excessive toxicity (and cost) suggests that this approach does not merit further investigation., (Copyright © 2011 Elsevier Ireland Ltd. All rights reserved.)

Introduction: Exisulind is an apoptotic agent with preclinical activity in non-small cell lung cancer (NSCLC). Vinorelbine is safe and effective in older patients with advanced NSCLC. We assessed these agents together as palliative treatment for older patients with advanced NSCLC., Methods: Chemotherapy-naive patients >/=70-years-old with stage IIIB-IV NSCLC and a performance status (PS) /=3 neutropenia occurred in 14/30 patients. Two patients experienced neutropenic fever. There were no complete responses, one partial response and 12 patients with stable disease as their best response. The objective response rate was 4.0% (95% CI: 0.1-20.4%). Phase II median time-to-progression was 4.7 months (95% CI: 3.1-9.3 months) and median OS was 9.6 months (95% CI: 6.6-19.1 months)., Conclusions: This combination is safe, seems to have activity in the elderly with advanced NSCLC and a PS

Purpose: To evaluate 74 Gy thoracic radiation therapy (TRT) with induction and concurrent chemotherapy in stage IIIA/B non-small-cell lung cancer (NSCLC)., Patients and Methods: Patients with stage IIIA/B NSCLC were randomly assigned to induction chemotherapy with either carboplatin (area under the curve [AUC], 6; days 1 and 22) with paclitaxel (225 mg/m(2); days 1 and 22; arm A) or carboplatin (AUC, 5; days 1 and 22) with gemcitabine (1,000 mg/m(2); days 1, 8, 22, and 29; arm B). On day 43, arm A received weekly carboplatin (AUC, 2) and paclitaxel (45 mg/m(2)) while arm B received biweekly gemcitabine (35 mg/m(2)) both delivered concurrently with 74 Gy of TRT utilizing three-dimensional treatment planning. The primary end point was survival at 18 months., Results: Forty-three and 26 patients were accrued to arms A and B, respectively. Arm B was closed prematurely due to a high rate of grade 4 to 5 pulmonary toxicity. The overall response rate was 66.6% (95% CI, 50.5% to 80.4%) and 69.2% (95% CI, 48.2% to 85.7%) on arm A and B, respectively. The median survival time (MST) and 1-year survival rate was 24.3 months (95% CI, 12.3 to 36.4) and 66.7% (95% CI, 50.3 to 78.7) and 12.5 months (95% CI, 9.4 to 27.6) and 50.0% (95% CI, 29.9 to 67.2) for arms A and B, respectively. The primary toxicities included esophagitis, pulmonary, and fatigue., Conclusion: Arm A reached the primary end point with an estimated MST longer than 18 months and will be compared with a standard dose of TRT in a planned randomized phase III trial in the United States cooperative groups.

Purpose: To assess the efficacy and toxicity of carboplatin, etoposide, and the bcl-2 antisense oligonucleotide oblimersen as initial therapy for extensive-stage small-cell lung cancer (ES-SCLC). bcl-2 has been implicated as a key factor in SCLC oncogenesis and chemotherapeutic resistance., Patients and Methods: A 3:1 randomized phase II study was performed to evaluate carboplatin and etoposide with (arm A) or without oblimersen (arm B) in 56 assessable patients with chemotherapy-naïve ES-SCLC. Outcome measures including toxicity, objective response rate, complete response rate, failure-free survival, overall survival, and 1-year survival rate., Results: Oblimersen was associated with slightly more grade 3 to 4 hematologic toxicity (88% v 60%; P = .05). Response rates were 61% (95% CI, 45% to 76%) for arm A and 60% (95% CI, 32% to 84%) for arm B. The percentage of patients alive at 1 year was 24% (95% CI, 12% to 40%) with oblimersen, and 47% (95% CI, 21% to 73%) without oblimersen. Hazard ratios for failure-free survival (1.79; P = .07) and overall survival (2.13; P = .02) suggested worse outcome for patients receiving oblimersen. These results hold when adjusted for other prognostic factors, such as weight loss, in multivariate regression analysis., Conclusion: Despite extensive data supporting a critical role for Bcl-2 in chemoresistance in SCLC, addition of oblimersen to a standard regimen for this disease did not improve any clinical outcome measure. Emerging data from several groups suggest that this lack of efficacy may be due to insufficient suppression of Bcl-2 in vivo. Additional evaluation of this agent in SCLC is not warranted.

Purpose: Increased expression of eicosanoids in cancer has been associated with adverse prognosis. We performed a randomized phase II trial to test the hypothesis that inhibitors of two eicosanoid pathways (cyclooxygenase-2 [COX-2], celecoxib and 5-lipoxygenase [5-LOX], zileuton) added to chemotherapy would improve outcome in advanced non-small-cell lung cancer (NSCLC)., Patients and Methods: Patients with advanced NSCLC, a performance status of 0 to 2, and no prior therapy were eligible. All patients received carboplatin area under the curve (AUC) 5.5 mg/mL x min day 1 + gemcitabine (1,000 mg/m(2)) days 1 and 8. Patients were randomly assigned to: (a) zileuton 600 mg PO qid, (b) celecoxib 400 mg PO bid, or (c) celecoxib and zileuton at the same doses. Immunohistochemical staining for COX-2 and 5-LOX was performed without knowledge of outcomes., Results: One hundred forty patients were entered and 134 were eligible and treated. There was no survival difference between the arms. COX-2 expression was a negative prognostic marker for overall survival (OS; hazard ratio [HR] = 2.51, P = .019 for index >or= 4; HR = 4.16, P = .005 for index = 9) for patients not receiving celecoxib. Patients with increased COX-2 expression (index >or= 4), receiving celecoxib had better survival than did COX-2-expressing patients not receiving drug (HR = .342, P = .005 for OS; HR = .294, P = .002 for failure-free survival). Multivariate analysis confirmed the interaction of COX-2 and celecoxib on survival. 5-LOX expression was neither prognostic nor predictive., Conclusion: This study failed to demonstrate the value of dual eicosanoid inhibition or benefit from either agent alone in addition to chemotherapy. However, a prospectively defined subset analysis suggests an advantage for celecoxib and chemotherapy for patients with moderate to high COX-2 expression.

Background: Carboplatin and gemcitabine are one standard regimen for patients with advanced non-small cell lung cancer (NSCLC). The oral proapoptotic agent exisulind is a cyclic guanosine monophosphate phosphodiesterase that increases apoptosis in vitro. We performed a phase II trial of carboplatin and gemcitabine with exisulind in patients with advanced NSCLC., Methods: Gemcitabine (1000 mg/m days 1 and 8) and carboplatin (AUC = 5 day 1) were administered every 21 days, with exisulind orally at 250 mg orally twice daily continuously, starting day 1. The primary objective was to evaluate the 18-month survival. Secondary objectives included response rate, progression-free survival, and toxicities. Eligibility included stage IIIB (pleural effusion) or stage IV NSCLC, no previous chemotherapy, and an Eastern Cooperative Oncology Group (ECOG) performance status (PS) of 0-1., Results: Of 57 eligible patients treated, 34 patients were male and 23 female, 42 had stage IV, six stage IIIB, and nine had recurrent disease. The median age was 63 years (range, 37-83). Twenty-six patients had an ECOG PS of 0 and 31 had a PS of 1. The majority of grade 3-4 toxicities were hematologic. Grade 3-4 nonhematologic toxicity seen in >5% of patients included nausea/vomiting in 16% and fatigue in 23% of patients. The overall response rate was 19.3%. Median progression-free survival was 4.7 months. Median overall survival was 9.0 months. Eighteen-month overall survival was 30%., Conclusion: The chemotherapy combination of gemcitabine and carboplatin with the oral proapoptotic agent exisulind is generally well tolerated with principally hematologic toxicity. The statistical endpoint of 17 patients alive at 18 months was met, but given ongoing developments in advanced NSCLC, ECOG will not be pursuing additional trials of exisulind in NSCLC.

Vinorelbine administered in a doublet with cisplatin has become a standard treatment in patients with advanced non-small cell lung cancer (NSCLC). However, carboplatin appears to provide comparable efficacy with a better nonhematologic safety profile than cisplatin. Herein we report the results of a phase I/II trial of weekly vinorelbine and divided-dose carboplatin in patients with stage IIIB/IV NSCLC, Eastern Cooperative Oncology Group performance status < or = 2, and adequate bone marrow. Patients received vinorelbine starting at 20 mg/m(2) (to 25 mg/m(2)) and carboplatin area under the curve (AUC) 2.5 in divided-doses, both given on Days 1 and 8 every 21-day cycle for up to 6 cycles or until disease progression. Dose-limiting toxicity was defined for Cycles 1 and 2. Tumor response and toxicity were assessed using standard criteria. Twenty-one patients with a mean age of 67 years (range, 43-79) and stage IIIB/IV (8/13) disease were enrolled. All but 1 patient were chemotherapy-nai;ve; the majority (n = 20) had good performance status (< or = 1). Seventy-nine courses (median, 4) were administered. The vinorelbine/carboplatin doublet was well tolerated, with 7 courses interrupted or delayed because of toxicity. Toxicities were generally mild and evenly divided between hematologic (i.e., neutropenia) and nonhematologic (i.e., fatigue). No growth factor support was required for hematologic toxicity. There was only one case of grade 2 alopecia, and no cases of > or = grade 2 neurotoxicity. There were 5 (24%) partial responses, and 9 (43%) patients had stable disease. Weekly vinorelbine 25 mg/m(2) and divided-dose carboplatin AUC 2.5 is a well tolerated regimen with activity in advanced NSCLC patients. Further evaluation of this regimen in combination with novel targeted biologic therapy is warranted., (Copyright 2002 Elsevier Science Ireland Ltd.)

Docetaxel has demonstrated activity in a broad range of solid tumors. Phase I trials have shown 100 mg/m(2) every 21 d to be the recommended dose. This phase I trial was designed to define the dose-limiting toxicities (DLTs) and maximum tolerated dose (MTD) of docetaxel with granulocyte colony-stimulating factor (G-CSF) support in patients with advanced solid tumors. Eligible patients had advanced malignancies and up to two prior chemotherapy regimens, ECOG PS = 0 1, adequate organ function, and gave written, informed consent. Docetaxel was escalated in cohorts of patients starting at 100 mg/m(2) on a 21-d schedule. Prophylactic G-CSF was administered on d 3 10. The DLT was defined as grade IV neutropenia >4 d, febrile neutropenia, grade IV thrombocytopenia, any grade III nonhematologic toxicity, or the inability to receive cycle 2 because of ongoing toxicity. Twenty-three patients were enrolled at doses up to 145 mg/m(2). The median age was 59 yr and the median number of prior chemotherapy regimens was 1. No DLT was observed at 100 mg/m(2), and 2 of 11 patients at 120 mg/m(2) experienced DLT (neutropenic fever and stomatitis). At 145 mg/m(2), one of eight patients had DLT (fatigue). Two of eight patients at 145 mg/m(2) had brief grade IV neutropenia (without fever), and none had grade III-IV thrombocytopenia or anemia. The docetaxel dose can be safely escalated to 145 mg/m(2) every 21 d with GCSF support, a 45% increase above the standard recommended phase II dose. Further studies will clarify the role of dose-intensified docetaxel.

This phase I study was designed to determine the maximum tolerated dose of carboplatin when administered in combination with a fixed dose of vinorelbine and concomitant radiation therapy in patients with advanced non-small cell lung cancer. Chemotherapy was administered on days 1 and 8 of two 21 day cycles. It consisted of vinorelbine at 15 mg/m(2) and carboplatin administered at an initial area under the curve (AUC) of 1.5, and increased by an AUC of 0.5 per dose level to a maximum AUC of 3, corresponding with an AUC of 6 per cycle of chemotherapy. Radiation was administered in daily fractions of 200 cGy over 5-7 weeks. We treated 36 patients, of whom 27 had stage II or III disease, and nine had stage IV disease but required thoracic radiation for palliation. Toxicities included neutropenia (three with Grade 4) and esophagitis (seven with Grade 3 and one with Grade 4). Four patients had radiation pneumonitis 4-7 months after completing therapy, three of whom died. The recommended phase II dose of carboplatin is an AUC of 3 on 2 consecutive weeks. Of 33 patients evaluable for response within the radiation field, 17 (52%) had complete or partial response, and 13 had stable disease. Of seven patients evaluable with distant metastatic disease, three had a complete or partial response, and two had stable disease. The median survival for the entire group and for patients with stage II/III disease was 13.5 months. We conclude that the combination of carboplatin, vinorelbine, and radiotherapy is feasible at these doses. It may be a useful alternative for patients not able to tolerate cisplatin-based therapy.

Purpose: We designed a phase I-II trial of three active agents, paclitaxel, ifosfamide, and vinorelbine, in advanced non-small-cell lung cancer (NSCLC) to: 1) define the dose-limiting toxicities (DLT) and maximum tolerated dose (MTD) of paclitaxel with filgrastim (G-CSF) support; and 2) determine the overall response rate and median survival of patients treated on this regimen., Patients and Methods: We treated cohorts of patients with stage IIIB or IV NSCLC with ifosfamide 1.2-1.6 g/m2/day x 3 and vinorelbine 20-25 mg/m2/day x 3 and escalating doses of paclitaxel at 100-175 mg/m2 on day 2 with G-CSF support on a 21-day cycle. One prior experimental single-agent chemotherapy regimen was allowed., Results: Fifty-six patients, were enrolled on this trial: 27 on the phase I portion of the study and an additional 29 at the recommended phase II dose (RPTD). Thirteen patients had received prior chemotherapy. Paclitaxel doses of 175 mg/m2 and 150 mg/m2 produced dose-limiting myelosuppression, and the RPTD was determined to be paclitaxel 135 mg/m2 with ifosfamide 1.2 g/m2/day on days 1-3 and vinorelbine 20 mg/m2/ day on days 1-3 with G-CSF support. The overall response rate was 18%, with a median survival of 6.1 months. Six of 35 patients (17%) treated at the RPTD achieved a partial response to therapy. Grade IV neutropenia was observed in 19 of 35 patients at this dose, with eight patients suffering febrile neutropenia., Conclusions: This non-cisplatin-containing three-drug regimen has substantial toxicity and low activity in advanced NSCLC, and does not seem to improve on prior regimens. It is unclear whether the lack of efficacy relates to an antagonistic reaction between the specific drugs, administration schedule, or to subtherapeutic doses of the individual agents.

Ifosfamide and vinorelbine have demonstrated single-agent activity against advanced non-small cell lung cancer. The dose-limiting toxicity of each agent is myelosuppression. Several trials have studied this combination to determine its toxicity and efficacy in non-small cell lung cancer. We conducted a dose-escalation study of vinorelbine in a novel (daily x 3) schedule with ifosfamide and granulocyte colony-stimulating factor support to define the dose-limiting toxicities and maximum tolerated dose of vinorelbine in this combination. Other investigators have studied this combination in the phase II setting. In our phase I study involving 42 patients, the recommended phase II dose was vinorelbine 30 mg/m2 with ifosfamide 1.6 g/m2, each given on 3 consecutive days, followed by granulocyte colony-stimulating factor. The overall response rate was 40%, with a median survival of 50 weeks. Myelosuppression proved to be dose limiting for this regimen, without other major toxicities. Other groups have studied the ifosfamide/vinorelbine combination, and studies adding cisplatin to this regimen have been conducted as well. Given the tolerable toxicity and encouraging response rates and 1-year survival rate seen with this regimen, further investigation of the ifosfamide/vinorelbine regimen has continued in a phase II Cancer and Leukemia Group B trial. Further study of the potential application of the combination as induction therapy for stage III disease is warranted.

The role of chemotherapy in the treatment of non-small cell lung cancer (NSCLC) has expanded in recent years, resulting in increased median survival and higher 5-year survival rates in some studies. Few patients with NSCLC can be cured, however, and the median survival time is still modest. Research strategies are aimed at identifying new active single agents, testing their combination in non-cisplatin- and non-carboplatin-containing regimens, and their incorporation into regimens containing more than two drugs, in efforts to improve response and survival and/or reduce toxicity. Several trials of triplet chemotherapy combinations for the treatment of NSCLC have been conducted at the University of Chicago. The three-drug regimen of vinorelbine, paclitaxel, and ifosfamide with granulocyte colony-stimulating factor was evaluated in a phase I trial. Doses of all three drugs were reduced from their standard doses so that toxicity would be manageable, although toxicity was still high. The low response rate (<20%) at the recommended phase II doses led to early closure of this trial. The University of Chicago is also assessing the three-drug combination of carboplatin, paclitaxel, and ifosfamide in patients with stage IIIB and IV NSCLC. The carboplatin and paclitaxel doses are being maintained within their active single-agent range, with the goal of identifying the maximum tolerated dose of ifosfamide when added to this combination. Additional end points include response rates, survival time, and dose-limiting toxicities. This study is ongoing.

Purpose: We designed a phase I dose-escalation study of vinorelbine on a novel (daily-times-three) schedule with ifosfamide with granulocyte colony-stimulating factor (G-CSF) support to define the dose-limiting toxicity (DLT) and maximum-tolerated dose (MTD) of vinorelbine in this combination., Patients and Methods: Cohorts of patients with stage IIIB or IV non-small-cell lung cancer (NSCLC) and no prior chemotherapy received vinorelbine starting at 15 mg/m2 on days 1, 2, and 3, and ifosfamide starting at 2.0 g/m2 on days 1, 2, and 3 with G-CSF support for all patients. Cycles were repeated every 21 days. Plasma vinorelbine concentrations were also analyzed., Results: Forty-two patients were treated. The median age was 58 years (range, 34 to 75) and 41 had a performance status of 0 or 1. The DLT was neutropenia and sepsis at a maximum-administered vinorelbine dose of 35 mg/m2 for 3 days. The recommended phase II dose was vinorelbine 30 mg/m2 with ifosfamide 1.6 g/m2 both given on 3 consecutive days. The overall response rate was 40% (17 of 42; all partial responders). The median survival duration was 50 weeks, with a 1-year survival rate of 48%. Pharmacokinetic analysis showed that vinorelbine in this combination and on this schedule is cleared 1.5 to two times faster than in single-agent once-weekly studies., Conclusion: Myelosuppression is the DLT of this regimen with no major subjective toxicities. With tolerable toxicity and an encouraging 1-year survival rate of 48%, further investigation of this new vinorelbine schedule is warranted in this and other combination regimens.

Two studies were performed to determine the maximum tolerated dose (MTD) of paclitaxel and vinorelbine, respectively, in combination with a fixed dose of ifosfamide in previously untreated patients with stage IIIB or IV non-small cell lung cancer. Response rate and survival were also assessed. Both regimens were given with mesna and granulocyte colony-stimulating factor support. The maximum tolerated dose of paclitaxel in combination with 1.6 g/m2/d X 3 ifosfamide was 300 mg/m2, and the recommended dose for phase II study is 250 mg/m2. Among 31 patients treated with ifosfamide/paclitaxel, there were seven partial responses; additionally, 10 patients had either minor regression or stable disease. The maximum tolerated dose of vinorelbine in combination with 1.6 g/m2/d X 3 ifosfamide was 35 mg/m2/d X 3, and the recommended dose for phase II study is 30 mg/m2/d X 3. Among 42 patients treated with ifosfamide/vinorelbine, responses have been encouraging, and final analysis is pending. The dose-limiting toxicity for both regimens was neutropenia. These findings indicate that ifosfamide-containing combination chemotherapy regimens have activity in advanced non-small cell lung cancer and are well tolerated when administered with granulocyte colony-stimulating factor.

Current clinical investigations in the palliative care setting for patients with non-small cell lung cancer are focused on new drugs and combinations. The goal of these studies is to identify more effective and/or less toxic therapy. At the University of Chicago, we have conducted phase I and II studies to integrate new single agents into novel combination chemotherapy regimens. Two such studies have combined the use of ifosfamide with either vinorelbine or paclitaxel. All these drugs have established single-agent activity in non-small cell lung cancer and a favorable toxicity spectrum. We describe the study rationale and design, and the preliminary data of these trials.

Vinorelbine (Navelbine; Burroughs Wellcome Co, Research Triangle Park, NC; Pierre Fabre Medicament, Paris, France), a semisynthetic vinca alkaloid, and ifosfamide have each shown activity as a single agent and in various combination-chemotherapy regimens against non-small cell lung cancer. Vinorelbine usually has been given on a once-weekly schedule. We designed a phase I study adding escalating doses of vinorelbine on a novel schedule of 3 consecutive days to ifosfamide in a dose-intensive regimen with granulocyte colony-stimulating factor. The goals were to define the dose-limiting toxicity and maximum tolerated dose of vinorelbine and to document the toxicity profile and the overall response and survival rates observed. Eligibility criteria included histologically or cytologically documented stage IIIB or stage IV non-small cell lung cancer, measurable or evaluable disease, and no prior chemotherapy. Treatment consisted of escalating doses of vinorelbine (starting at 15 mg/m2) on days 1, 2, and 3 and ifosfamide at 2 g/m2 and decreased to 1.6 g/m2 on days 1, 2, and 3. Granulocyte colony-stimulating factor was administered subcutaneously at 5 micrograms/kg on days 5 through 11 in all patients. Cycles were repeated every 21 days. Forty-two patients were treated. The median age was 58 years (age range, 34 to 75 years); 41 patients had a performance status of 0 or 1. Dose-limiting neutropenia was observed in two of three patients at the initial dose level of ifosfamide 2 g/m2 and vinorelbine 15 mg/m2. Ifosfamide was therefore decreased to 1.6 g/m2, and vinorelbine was subsequently escalated, with a maximum administered dose of 35 mg/m2. The recommended phase II dose was ifosfamide 1.6 g/m2 on days 1, 2, and 3 with vinorelbine 30 mg/m2 on days 1, 2, and 3, given with granulocyte colony-stimulating factor support, on a 21-day cycle. At the recommended phase II dose myelosuppression remained the most common toxic effect, with grade 3 or 4 neutropenia of brief duration occurring in 20 patients. Final analysis has not yet been completed, but responses have been observed at several dose levels. The maximum tolerated dose of vinorelbine given on days 1, 2, and 3 is 30 mg/m2 when given with ifosfamide at 1.6 g/m2 on days 1, 2, and 3 and granulocyte colony-stimulating factor support. Myelosuppression is the dose-limiting toxic effect. Future analyses of the data will report the overall response and survival rates in these patients.

Most patients with advanced solid tumors of the chest will have local and/or distant disease progression despite standard therapy. Vinorelbine (Navelbine; Burroughs Wellcome Co, Research Triangle Park, NC; Pierre Fabre Medicament, Paris, France) is a new semisynthetic vinca alkaloid with single-agent activity in lung cancer that recently also has been shown to act as a radiosensitizer in vitro. This study aims to define the maximum tolerated dose and dose-limiting toxicity when vinorelbine is given with cisplatin and concomitant radiation therapy. To date, 25 patients with advanced malignancies of the chest have been treated in a dose-escalation trial of vinorelbine administered once weekly with cisplatin (100 mg/m2 every 21 days) and concomitant thoracic radiation therapy (2 Gy/d x 30 fractions for 60 Gy). Vinorelbine was initially given at 20 and 25 mg/m2/wk. Acute dose-limiting toxicity was myelosuppression, which was seen at a vinorelbine dose of 25/mg/m2/wk, with grade 4 neutropenia in two of three patients and one treatment-related death from neutropenic sepsis. At vinorelbine 20/mg/m2/wk, no acute dose-limiting toxicity was seen, but grade 3 or 4 esophagitis developed in three of six patients near the end or after completion of radiation therapy. We subsequently decreased the administration of vinorelbine to weeks 1, 2, 4, and 5. Tolerance appears to be greater with this schedule; however, severe or life-threatening esophagitis at the completion of therapy continues to be observed. Given these preliminary results, it appears feasible to treat patients with advanced chest malignancies with concomitant cisplatin, vinorelbine, and radiation therapy. The significant dose reduction of vinorelbine that is necessary with concomitant radiation therapy provides the first in vivo evidence of a strong radiosensitizing effect of vinorelbine. The schedule is currently being modified to reduce the incidence of esophagitis.

Background: Ifosfamide and paclitaxel are active drugs in the management of non-small-cell lung cancer. We have performed a phase I study using a fixed dose of ifosfamide with escalating doses of paclitaxel, with G-CSF support, in an effort to determine the maximum tolerated dose (MTD) of paclitaxel in this combination, and to describe the dose-limiting toxicities of the combination at the recommended phase II dose of paclitaxel. We also studied the feasibility of delivering the paclitaxel as a one-hour infusion at the recommended phase II dose., Patients and Methods: Thirty-one patients were treated, 25 with stage IV disease, and 6 with stage IIIB disease. Ifosfamide was administered at a dose of 1.6 g/m2 i.v. bolus daily x 3 days, with mesna uroprotection. Paclitaxel was administered as a 24-hour infusion at dose levels of 135, 170, 200, 250, and 300 mg/m2; six patients were treated with a one-hour infusion, at a dose of 250 mg/m2. G-CSF, 5 micrograms/kg, was administered subcutaneously on days 4 through 10, or until the absolute neutrophil count exceeded 4000/microliters. Cycles were repeated every 21 days., Results: The dose-limiting toxicity was granulocytopenia, which increased with increasing dose levels of paclitaxel. The MTD was 300 mg/m2 of paclitaxel, and the recommended phase II dose 250 mg/m2 administered as a 24-hour infusion. Other toxicities were generally mild, with only 5 patients demonstrating grade 3 neurotoxicity and 5 with grade 3 thrombocytopenia. Partial responses were seen in seven patients (23%), all in the 18 patients who received dose levels of 250 mg/m2 or higher., Conclusions: Ifosfamide plus paclitaxel is an active treatment regimen in advanced non-small-cell lung cancer, and compares favorably with the results of cisplatin-based chemotherapy. A phase II study is in progress by the Cancer and Leukemia Group B, in an effort to better characterize the tolerance of the regimen, as well as its effect on tumor response and survival.

Purpose: The combination of cisplatin, 5-fluorouracil, and leucovorin (PFL) has been reported to have a 29% response rate in advanced non-small cell lung cancer. Vinorelbine, a semi-synthetic vinca alkaloid, has also been reported to have single-agent activity in this disease. We designed a phase I-II study in which escalating doses of vinorelbine were added to PFL to define the dose-limiting toxicity and maximum tolerated dose of vinorelbine, and to determine the response rate and survival at the recommended phase II dose., Patients and Methods: This study enrolled patients between December 1991 and August 1993. Eligibility criteria included histologically or cytologically documented stage III or IV non-small cell lung cancer, measurable or evaluable disease, and no prior chemotherapy. Treatment consisted of escalating doses of vinorelbine (starting at 20 mg/m2) on days 1 and 6, cisplatin 100 mg/m2 on day 2, and 5-fluorouracil as a continuous infusion at 800 mg/m2/day for 4 days (days 2-5) with leucovorin 100 mg orally every 4 hours on days 1 through 5. Cycles were repeated every 21 days., Results: Forty patients were treated during the study. The median age of the patients was 58 (range, 33-75) and 36 patients had a performance status of 0 or 1. Dose-limiting neutropenia was observed in both patients treated with vinorelbine at 25 mg/m2. At the recommended phase II vinorelbine dose of 20 mg/m2 on days 1 and 6, myelosuppression remained the most common toxicity, with 22 patients (55%) having grade 4 neutropenia. Fifteen patients (38%) required hospital admission for neutropenic fever; two died of neutropenic sepsis. Of 33 patients evaluated, 2 patients achieved a complete response and 10 patients achieved a partial response (overall response rate, 30%; 36% of the evaluated patients). Median survival was 10.4 months for the entire cohort (16.4 months for those with stage III disease and 9.6 months for patients with stage IV disease) and 1-year survival was 45%. The overall median time to progression was 8.1 months., Conclusions: The maximum tolerated dose of vinorelbine given on days 1 and 6 with PFL is 20 mg/m2; myelosuppression is the dose-limited factor. The response rate is similar to rates observed in prior studies of combination chemotherapy, but the median survival of patients with stage IV disease exceeds that of many other regimens.

Both paclitaxel and ifosfamide have significant single-agent activity in non-small cell lung cancer. We designed a phase I study combining escalating doses of paclitaxel, administered by 24-hour infusion, with ifosfamide given at a dose of 1.6 g/m2 daily x 3. Paclitaxel dose levels were 135, 170, 200, 250, and 300 mg/m2. The goal of the study was to determine the maximum tolerated dose and dose-limiting toxicities of paclitaxel when used in this combination. Dose escalation was possible because of the use of filgrastim, a granulocyte colony-stimulating factor. Twenty-five patients at three institutions were treated. The dose-limiting toxicity of the combination was granulocytopenia, with other toxicities being generally mild to moderate. The maximum tolerated dose of paclitaxel was 300 mg/m2, and the recommended phase II dose is 250 mg/m2. There was a suggestion of a dose-response curve with paclitaxel as all three partial responses were seen at the 250 mg/m2 dose level. An additional II patients had objective regression or stable disease lasting for 9 to 30 weeks. A phase II study of this combination is currently being planned by the Cancer and Leukemia Group B.